Ferric Carboxymaltose-Induced Hypophosphatemia: Definition, Prevalence, and Clinical Impact
Ferric carboxymaltose (FCM) causes moderate to severe hypophosphatemia in 47-75% of patients due to its specific physicochemical properties triggering increased FGF23, which can lead to serious complications including osteomalacia and fractures with repeated use. 1
Definition of Hypophosphatemia
Hypophosphatemia is classified by severity based on serum phosphate levels:
- Mild: < lower limit of normal - 2.5 mg/dL 1
- Moderate: < 2.5 - 2.0 mg/dL 1
- Severe: < 2.0 - 1.0 mg/dL 1
- Potentially life-threatening: < 1.0 mg/dL 1
Prevalence and Mechanism
- FCM causes hypophosphatemia in 47-75% of patients, with 51% developing levels <2 mg/dL within 35 days of administration 1
- The specific physicochemical properties of FCM trigger a sharp increase in intact fibroblast growth factor 23 (iFGF23) 1
- Elevated iFGF23 leads to hyperphosphaturic hypophosphatemia through increased urinary phosphate excretion 1
- This creates a cascade of biochemical changes known as "6H-syndrome": high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism 1
- The hypophosphatemia can persist for up to 6 months following administration 1
Clinical Impact and Symptoms
- Moderate hypophosphatemia commonly causes symptoms including fatigue, proximal muscle weakness, and bone pain 1
- These symptoms can mimic iron deficiency anemia, making diagnosis challenging 1
- Additional symptoms may include asthenia, myopathy, and in severe cases, respiratory failure 1
- Prolonged hypophosphatemia can lead to osteomalacia, fractures, and bone deformities 1, 2
- Case reports document patients requiring hospitalization and extended phosphate supplementation (up to 16 weeks) 3
- Severe hypophosphatemia can cause insufficiency fractures of the sacrum and vertebrae 2
Risk Factors
Patients at highest risk include those with:
- Recurrent or ongoing blood loss (abnormal uterine bleeding, hereditary hemorrhagic telangiectasia, GI bleeding) 1
- Malabsorptive disorders (bariatric surgery, inflammatory bowel disease, celiac disease) 1
- Normal renal function (higher GFR increases phosphate excretion) 1
- Severe iron deficiency 1
- Lower body weight 1
- Low baseline serum phosphate 1, 4
- Higher serum PTH 1
- Pre-existing vitamin D deficiency 4
Management Recommendations
- The most important management step is cessation of FCM in patients who develop hypophosphatemia 5
- For mild asymptomatic hypophosphatemia, observation is recommended 1, 5
- Treatment should focus on mitigating secondary hyperparathyroidism with vitamin D supplementation 1, 5
- Phosphate repletion should be avoided as it raises parathyroid hormone and worsens phosphaturia 1, 5
- FDA mandates monitoring serum phosphate levels in patients at risk for chronic low serum phosphate 1
- Consider alternative IV iron formulations in high-risk patients, as other preparations (ferumoxytol, iron sucrose) have much lower rates of hypophosphatemia (<10%) 1
Prevention and Monitoring
- Screen for risk factors before administering FCM 1, 4
- Monitor phosphate levels in patients receiving repeat courses of treatment 1
- Educate patients to report symptoms like worsening fatigue, muscle pain, or bone pain following infusion 1, 4
- Consider alternative IV iron formulations for patients requiring repeated infusions 1, 6
- Vitamin D supplementation before FCM infusion does not reduce hypophosphatemia risk 1
Clinical Pitfalls
- Symptoms of hypophosphatemia can mimic iron deficiency anemia, leading to misdiagnosis 1, 4
- The condition is often underrecognized despite being common 4
- Product labeling may describe hypophosphatemia as "transient and asymptomatic," but evidence shows it can be severe, symptomatic, and prolonged 4
- Repeated FCM infusions in high-risk patients can lead to osteomalacia and fractures 1, 2
- Overdosage of FCM (as noted in the FDA label) can lead to hemosiderosis and hypophosphatemic osteomalacia 7